Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs) while others develop ATL or HAM/TSP with no effective treatment, vaccine or cure. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells' dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family play critical role in regulating antigen-specific immune responses, and it is becoming increasingly evident that blocking multiple inhibitory receptors simultaneously improves T-cell based therapies. Therefore, we propose to investigate a comparative co-expression pattern of key IgSF negative regulators among carriers versus patients followed by standardizing of a blockade strategy to restore polyfunctionality, immune homeostasis, and cytolytic potential of antigen-specific T cells in HTLV-1 patient cohorts. To project advantage, this kind of therapeutic measure has shown promising results in other human diseases; however, it needs to be evaluated with respect to neuroinflammatory diseases especially those associated with chronic infection for which HTLV-1 provides a good model. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Thus, we will identify a panel of HTLV-1 epitopes directly from the infected cells and validate in ACs to select potential neoepitopes capable of initiating a polyclonal response in chronically infected patients. The selected candidates from both approaches will then be coupled in a combined immunotherapy, which will be evaluated pre-clinically in a humanized (BLT) mouse model of HTLV-1 chronic infection. Our central hypothesis is that a combined immunotherapy coupled with immune checkpoint blockers and neo-epitopes derived from infected cells will restore existing T-cell functions while expanding protective CTLs in chronically infected patients. As a result of this, HTLV-1 proviral load and concomitant Tax expression will be reduced leading to decreased antigen threshold for the expansion of T cells with dysregulated functions and exhausted phenotype. The restoration of positive immunity within periphery will also lead to the reduced accumulation of activated T cells and inflammation within the CNS potentially ameliorating the disease. These studies will strengthen the potential of immunotherapeutic treatment options for HTLV-1 and will impact our understanding of other chronic infectious diseases of broader impact such as those associated with HBV, HCV, HIV-1, etc.